| 15-Deoxy-Delta(12,14)-prostaglandin-J(2) reveals a new pVHL-independent, lysosomal-dependent mechanism of HIF-1alpha degradation. | |
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MedLine Citation:
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PMID: 19458911 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia-inducible factor-1alpha (HIF-1alpha) protein is degraded under normoxia by its association to von Hippel-Lindau protein (pVHL) and further proteasomal digestion. However, human renal cells HK-2 treated with 15-deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)) accumulate HIF-1alpha in normoxic conditions. Thus, we aimed to investigate the mechanism involved in this accumulation. We found that 15d-PGJ(2) induced an over-accumulation of HIF-1alpha in RCC4 cells, which lack pVHL and in HK-2 cells treated with inhibitors of the pVHL-proteasome pathway. These results indicated that pVHL-proteasome-independent mechanisms are involved, and therefore we aimed to ascertain them. We have identified a new lysosomal-dependent mechanism of HIF-1alpha degradation as a target for 15d-PGJ(2) based on: (1) HIF-1alpha colocalized with the specific lysosomal marker Lamp-2a, (2) 15d-PGJ(2) inhibited the activity of cathepsin B, a lysosomal protease, and (3) inhibition of lysosomal activity did not result in over-accumulation of HIF-1alpha in 15d-PGJ(2)-treated cells. Therefore, expression of HIF-1alpha is also modulated by lysosomal degradation. |
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Authors:
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Gemma Olmos; María I Arenas; Raquel Bienes; María Jose Calzada; Julián Aragonés; Maria Laura Garcia-Bermejo; Manuel O Landazuri; Javier Lucio-Cazaña |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-05-21 |
Journal Detail:
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Title: Cellular and molecular life sciences : CMLS Volume: 66 ISSN: 1420-9071 ISO Abbreviation: Cell. Mol. Life Sci. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-06 Completed Date: 2009-07-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9705402 Medline TA: Cell Mol Life Sci Country: Switzerland |
Other Details:
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Languages: eng Pagination: 2167-80 Citation Subset: IM |
Affiliation:
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Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, 28471, Alcalá de Henares, Madrid, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcium / metabolism Calpain / metabolism Cathepsin B / metabolism Cell Line Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics, metabolism* Kidney / cytology Lysosomes / metabolism* Prostaglandin D2 / analogs & derivatives*, metabolism Von Hippel-Lindau Tumor Suppressor Protein / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/15-deoxy-delta(12,14)-prostaglandin J2; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 41598-07-6/Prostaglandin D2; 7440-70-2/Calcium; EC 3.4.22.-/Calpain; EC 3.4.22.1/Cathepsin B; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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